FROM
GENOME COMPARISONS, UCSD RESEARCHERS LEARN LESSONS ABOUT EVOLUTION AND
THE FIGHT AGAINST CANCER

In 1905, American astronomer Percival Lowell
predicted the existence of a new planet he called Planet X. Lowell proved
that this new planet existed even though no one had been able to see it
in the sky. Twenty-five years later, Arizona astronomer Clyde Tombaugh
stumbled on images of X from the Flagstaff Observatory. Today, that planet
is known as Pluto.

While it took twenty-five years for astronomers to go from
theory to confirmation of Pluto’s existence, it took genome scientists
barely three months in 2003 to confirm a revolutionary new view of what
happens in the human genome to cause dramatic evolutionary changes. Now
bioinformaticians at the University of California, San Diego (UCSD)—who
posited that ‘fragile’ regions exist in the human genome that
are more susceptible to gene rearrangements—are collaborating with
biologists to see if their new theory can yield potentially life-saving
insights into diseases such as breast cancer, in which chromosomal rearrangements
are implicated.

"It took only three months to go from theory to hard
scientific evidence that there are regions of the genome that are subject
to evolutionary ‘earthquakes’ over and over again," says
Pavel Pevzner, who holds the Ronald R. Taylor Chair in computer science
and engineering at UCSD’s Jacobs School of Engineering. "That
is representative of how quickly knowledge is advancing in bioinformatics,
and how useful this research can be for medicine and other fields."

In June, Pevzner and UCSD mathematics professor Glenn Tesler
predicted the existence of evolutionary ‘fault zones’ –
hotspots where gene rearrangements are more likely to occur and change
the architecture of our genomes. Their work was based on computational
analysis and comparison of the human and mouse genomes. In a paper in
the journal Proceedings of the National Academy of Sciences (PNAS),
Pevzner and Tesler estimated that these fault zones may be limited to
approximately 400 ‘fragile’ regions that account for only
5 percent of the human genome. While reaching that estimate using computers,
the researchers were not yet able to point to specific locations in the
genome where these rearrangements are more commonplace.

The PNAS paper departed from the prevailing ‘random
breakage’ theory of evolution that has been widely held for nearly
two decades, but the theory of ‘fragile breakage’ quickly
gained acceptance. A team led by UC Santa Cruz scientists Jim Kent and
David Haussler—who are widely credited for their work in the public-sector
assembly of the human genome—were the first to confirm the UCSD
results. In addition, for the first time, they explicitly pinpointed the
location of some of the faults in the human genome.

Kent’s findings were published in the September 30
edition of PNAS, along with a commentary by two pioneers in computational
biology: University of Ottawa mathematician David Sankoff, and Case Western
Reserve University genetics professor Joseph Nadeau. The commentary supports
the original conclusions of Pevzner and Tesler. That support is all the
more notable, because Nadeau is the scientist who originated
the random breakage theory in the mid-1980s that Pevzner and Tesler rebutted.
In their article, he and Sankoff acknowledge that the random breakage
theory needs to be revised along the lines spelled out by Pevzner and
Tesler.

Using similar computational tools, Pevzner and his post-doctoral
researcher, Ben Raphael, are working with biologists at the University
of California, San Francisco (UCSF) Cancer Center to analyze chromosomal
rearrangements in tumors. Their October paper in the journal Bioinformatics
includes an analysis that yields the first high-resolution (albeit incomplete)
picture of the genomic architecture of a complex breast cancer genome.

Human cancer cells frequently possess chromosomal aberrations (such as
missing an arm of a chromosome), or rearrangements leading to changes
in genomic architecture. The breast cancer MCF7 cell line is an extreme
example of such aberrations, where everything went wrong and all human
chromosomes but one got rearranged, fused together, or broken, as if a
tall building collapsed after an earthquake. Using the recently developed
End Sequence Profiling (ESP) technique developed at UCSF Cancer Center
that is cheaper and quicker than outright genome sequencing, Pevzner and
colleagues analyzed human MCF7 tumor cells and derived 22 genomic rearrangements
implicated in cancer, most of them previously unknown. Many of them have
already been experimentally confirmed at UCSF. The UCSF team has extended
this work to brain, ovarian, and prostate cancer cells, generating a tenfold
increase in the ESP data that Pevzner and Raphael are now analyzing.

“When the letters of our genomic alphabet get
scrambled in a single lifetime, it can be life-threatening,” says
Pevzner. “But

we suspect that
by understanding how genomic rearrangements
play out over millions of years of human evolution, we may find a correlation
between these phenomena—and possibly provide biologists with new
tools to study such conditions as breast cancer at the genetic level.”

As soon as reconstructions of other tumor genomes are completed,
Pevzner and his colleagues will investigate whether the breakpoints implicated
in cancers are correlated with the breakpoints evident in human-mouse
evolution from their common ancestor 75 million years ago. And as other
mammalian genomes are sequenced, Pevzner and Tesler expect to use advanced
computational tools to derive further insights into human evolution and
cancer.